This challenge project is based on (a) our pioneering work on IRGM as an autophagy factor 1, and (b) the genetic linkage recognition 2 of the role of autophagy and IRGM in Crohn's disease. The main objective is two-fold: (I) to delineate the role of autophagy in Crohn's disease etiology and pathogenesis, and (II) to determine specifically the mechanism of IRGM isoform action at the cellular level. This challenge project will in two years: (a) move forward the entire field of autophagy in immunity, infectious disease, and chronic inflammatory illnesses, with a special emphasis on mucosal immunity and inflammation of the gut, and (b) close a specific knowledge gap on how autophagy genetic polymorphisms in human populations predispose to the prevalent form of inflammatory bowel disease (IBD) known as Crohn's disease. The proposed relationships can and will be tested in 2 years. At the end of this grant we will have (i) a whole new view understanding of how autophagy works in mucosal immunity in association with IBD, and (ii) very specific knowledge regarding what role IRGM plays in Crohn's disease. Not only will the results of this project improve our understanding of the role of autophagy in mucosal immunity and IBD, but a compelling case will be built for the repurposing of the safe drug rapamycin for clinical trials in Crohn's disease. 1 Singh, S.B., Davis, A.S., Taylor, G.A. &Deretic, V. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science 313, 1438-1441 (2006). 2 Parkes, M. et al. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet 39, 830-832 (2007) PUBLIC HEALTH RELEVANCE: In the US, 500,000 people are suffering from Crohn's disease, a debilitating chronic inflammatory illness of the intestine that often requires surgery due to intestinal obstruction. We had been studying a gene called IRGM before it was linked through genetic studies with Crohn's disease. We discovered that this gene controls a process called autophagy that acts to cleanse the interior of all cells in our body, including those of the gut, and rids them of festering intracellular bacteria and inflammatory microbial products. In this project, we will determine how mutations in the IRGM gene in patients with Crohn's disease affect autophagy, and how this leads to inflammation of the intestine and progressive tissue pathology and destruction. We will be able to decipher this in a 2 year time period by studying blood cells and surgical resection tissues from the gut of Crohn's disease patients and analyzing IRGM function in autophagy in these specimens. As a final product two years from now, based on the knowledge acquired through this work, doctors will be able to begin clinical trials with currently existing FDA approved drugs to increase or decrease autophagy in patients, and help cure those afflicted by Crohn's disease.